Development of LRRK2 PROTAC degraders as chemical probes and potential lead compounds for the treatment of Parkinson's disease

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Parkinson's Disease (PD) is the second most common neurodegenerative disorder worldwide and no treatment is currently available to halt the onset and/or progression of PD pharmacologically. The kinase-activating G2019S mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) is one of the most common genetic causes of PD and has motivated work to develop LRRK2-targeted therapies, including LRRK2 kinase inhibitors. However, current LRRK2 kinase inhibitors, albeit in clinical trials, promote LRRK2 and microtubule association, underlying potential undesirable side effects. Alternative LRRK2-targeting strategy, known as LRRK2 Proteolysis Targeting Chimera (PROTAC) is therefore proposed. LRRK2 PROTACs are heterobifunctional small molecules that consist of a ligand that binds LRRK2, conjugated to a ligand that binds an E3 ubiquitin ligase via a linker. By recruiting a E3 ubiquitin ligase in close proximity to a LRRK2 protein, LRRK2 PROTACs can induce the ubiquitination and subsequent degradation of LRRK2 through the ubiquitin-proteasome pathway. By designing and synthesizing a few sets of LRRK2 PROTAC compounds and screening them with degradation assays on multiple cell lines, we identified potent LRRK2 PROTACs that degraded LRRK2 at nanomolar range concentrations. The goal of this fellowship is to further improve the potencies of these LRRK2 PROTACs through structural modification and qualify them as chemical probes and potential lead compounds for the treatment of PD by detailed in vitro and in vivo characterization and PD-related biology studies.